The migration and transport of leukocytes from blood vessels into diseased tissues is involved in the initiation of normal disease-fighting inflammatory responses. The process, also known as leukocyte recruitment, is also related to the onset and progression of inflammatory and autoimmune diseases. The resulting pathology of these diseases derives from the attack of the body's immune system defenses on normal tissues. Accordingly, preventing and blocking leukocyte recruitment to target tissues in inflammatory, autoimmune disease and cancer would be an effective approach to therapeutic intervention.
The infiltration of monocytes/macrophages into sites of inflammation is related to proteins, such as monocyte chemoattractant protein-1 (MCP-1, CCL2). Macrophages produce chemokines, such as macrophage inflammatory protein-1-beta (MIP-1β, CCL4). Such proteins interacts with chemokine receptors, for example, CCR2 and CCR5. Modulation, such as antagonism or inhibition, of CCR2 or CCR5 would be helpful to treat a wide range of diseases.
The identification of compounds that modulate the activity of chemokine receptors represents a desirable drug design approach to develop pharmacological agents for the treatment of diseases associated with chemokine receptor activity. The compounds of the present invention help fulfill these and other needs.